Caffeine is the single most widely consumed behaviorally-active substance in the world. In the United States, estimated per capita intake of caffeine approaches an average of 200 mg daily, mainly from dietary sources. Despite these statistics there have been surprisingly few studies of the behavioral consequences of chronic caffeine intake. Daily administration of caffeine results in tolerance to behavioral actions of the drug and perhaps physical dependence as well, facts not generally appreciated. Experiments are proposed to continue and expand upon ongoing research directed toward defining tolerance to behavioral effects of caffeine. Behavioral changes will be correlated with changes in brain neurotransmitter systems (e.g., adrenergic and adenosine) that have ben implicated in actions of caffeine in order to determine molecular mechanisms of drug action. Most studies will be performed on rats receiving scheduled-access to water bottles containing caffeine solution, and consuming approximately 70 mg/kg/day of drug. Matched controls will receive scheduled- access to drug-free tap water. Behavioral variables will include locomotor activity, food-reinforced schedule-controlled behavior, and drug discrimination. Temporal and pharmacologic parameters of caffeine tolerance will be determined, such as rate of development, surmountability, and cross-tolerance or otherwise altered sensitivity to various prototypic drugs. In order to begin examining the generality of findings in the rat, observations on caffeine effects on locomotor activity and drug discrimination will be extended to a primate species, the squirrel monkey. Experiments will be performed to determine the direct effects of caffeine on responses mediated by noradrenergic receptors (e.g., production of inositol phosphates) and on tyrosine hydroxylase activity on rat brain tissue in vitro. in addition, neurochemical parameters in discrete areas of rat brain will be correlated with behavioral changes in rats during caffeine tolerance and withdrawal. These parameters will include density and responsiveness of adenosine receptors, responsiveness of adrenergic receptors to norepinephrine, tyrosine hydroxylase activity in noradrenergic and dopaminergic neurotransmitter systems, and potassium-stimulated release of catecholamines.